The Regulation of Inteins: Adaptations in Extremophiles and Targets for Drug Discovery - Inteins are intervening proteins that catalyze their excision from flanking proteins, or exteins, via protein
splicing. Many inteins are mobile and can be inserted into intein-less alleles as initiated by an intein-
encoded homing endonuclease. Although the canonical mechanism of protein splicing is understood, the
role that inteins play for the host, if any, and the molecular means by which inteins adapt to extreme
environments are not fully elucidated. Using a combination of in vitro enzymology, structural biology,
screening for small molecule modulators, and genetic manipulation of intein-containing proteins,
undergraduate students will investigate how chemical or physical cues influence the structure and function
of inteins from extremophiles and if this conditional splicing is physiologically relevant. We will learn how
halophile inteins, encoded by mobile genes, have evolved to adapt to a highly saline environment. We will
determine if inteins are more than molecular parasites by discovering if an intein that is fixed in the
population can play a positive role for the host rather than exerting a fitness cost. We will design an assay to
discover a new category of splicing inhibitors to block the folding of intein enzymes, and learn if these
inhibitors affect growth of the host.
The long-term goal of the program is to understand how intein enzymes are able to catalyze chemical
reactions and maintain structural stability under conditions that would irreversibly denature eukaryotic or
prokaryotic proteins, and to determine if inteins can play a role for the host organism rather than being
molecular parasites. We want to discover inhibitors of the splicing process and determine if these inhibitors
can prevent the splicing of key proteins in environmental and human pathogens. Inteins have found wide
use in biotechnology applications, and a better understanding of their mechanism and structure may lead to
the development of better tools for biomedical research.
